Mitochondrial Carbonic Anhydrase VA Deficiency Resulting from CA5A Alterations Presents with Hyperammonemia in Early Childhood
Mitochondrial Carbonic Anhydrase VA Deficiency Resulting from CA5A Alterations Presents with Hyperammonemia in Early Childhood
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DOI：
10.1016/j.ajhg.2014.01.006
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发表时间：
2014-03-06
影响因子：
9.8
通讯作者：
Stockler-Ipsiroglu, Sylvia
中科院分区：
文献类型：
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作者：
van Karnebeek, Clara D.;Sly, William S.;Stockler-Ipsiroglu, Sylvia
四名儿童在三个无关的家庭（一个血缘关系）出现嗜睡，高乳酸血症，高血氨症的原因不明，在新生儿期和幼儿期。我们鉴定并验证了三种不同的CA5A改变，包括两个同胞中的纯合错义突变（c.697T> C）、导致外显子4跳跃的纯合剪接位点突变（c.555G> A）和外显子6的纯合4kb缺失。纯合突变c.697T> C（p.Ser233Pro）的有害性质通过酶活性降低和温度敏感性增加来证明。碳酸酐酶VA（CA-VA）是缺乏在肝脏中的纯合子外显子6缺失的儿童。受影响个体的代谢物谱符合CA-VA缺乏症，显示出参与中间代谢关键途径的四种酶的碳酸氢盐供应受损的证据：氨甲酰磷酸合成酶1（尿素循环），丙酮酸羧化酶（回补，异源生成），丙酰辅酶A羧化酶和3-甲基巴豆酰辅酶A羧化酶（支链氨基酸羧化酶）。在接受卡谷酸给药的3例儿童中，高氨血症消退。因此，在新生儿和幼儿高氨血症的鉴别诊断中，应将CA-VA缺乏症与尿素循环缺陷、有机酸尿症和丙酮酸羧化酶缺乏症一起作为可治疗的疾病。
Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood. We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6. The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity. Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion. The metabolite profiles in the affected individuals fit CA-VA deficiency, showing evidence of impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain amino acids catabolism). In the three children who were administered carglumic acid, hyperammonemia resolved. CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child.